Non-invasive magnetic resonance imaging (MRI) provides anatomical details for diagnosis and offers a highly resolved contrast between the specific tissues or organs of interest. The MR contrast enhancement agents improves both the quality of images obtained in an MR imaging procedure and the efficiency with which such images can be gathered. The use of MR contrast enhancement agents in MR imaging protocols has proven to be a valuable addition to the MRI technique.
Various metal chelates may serve as MR contrast enhancement agents, however the toxicity of free metal ions, stability of metal-chelate complex, and rapid rate of clearance of the chelates from the body during the imaging procedure are a few of the disadvantages associated with metal chelates. For example, while gadolinium (Gd) chelates are non-toxic, the Gd metal in free ionic form is toxic. For manganese (Mn)-chelate, dissociation of the chelating ligand from the metal center happens, which is also not desirable. As such, considerable efforts have been made to increase the efficiency and reduce the latent toxicity of the existing contrast enhancement agents. In comparing metal chelates, the contrast enhancement agents comprising iron (Fe) is an attractive alternative as compared to contrast agents with other metals, and one of the reasons is biocompatibility of Fe. This has led to increased interest in the use of iron-based materials as contrast agents for MRI.
The image quality of an agent may be increased by incorporating a moiety within the agent, wherein the moiety increases the agent size or targets a disease related biomarker. Either of these approaches improves selective localization of the agent at a diseased tissue lesion. This incorporation may be accomplished by the use of a bifunctional chelate, which binds to the metal as well as to a second moiety. The examples of iron-based bifunctional chelates are EDTA and deferoxamine, however, these chelates either pose a safety concern as they are redox active or have an insufficient MR signal. Furthermore, the known chelates employ isocyanate and isothiocyanate conjugation chemistries to attach a second moiety, which are hydrolytically sensitive functionalities that provide unstable conjugates in-vivo.
The alternative forms of bifunctional chelates and alternative methods of attaching a second moiety to an agent to enable bifunctionality is a long felt need. Therefore, a contrast enhancement agent comprising a bifunctional chelate having high in vitro and/or in vivo stability, prompt clearance from the body, ability to generate improved image quality at lower patient dosages, greater patient tolerance and safety for higher doses is highly desirable.